The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.

Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.

A unique case of right-sided Poland syndrome with true dextrocardia and total situs inversus.

Poland syndrome has been reported to be associated with true dextrocardia, but not with true situs inversus. In this report, we describe the first patient with total situs inversus in medical literature and try to highlight the syndrome's probable etiology and pathogenetic mechanisms in utero.

Otosclerosis and vitamin D receptor gene polymorphism.

OBJECTIVE: The possible genetic relationship between otosclerosis and Vitamin D Receptor (VDR) gene polymorphism is uncertain. The aim of this study is to assess association between otosclerosis and VDR gene polymorphisms. STUDY DESIGN: Case-control Studies. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Clinical diagnosis of stapes fixation was based on otoscopic, audiometric, tympanometric and surgical findings. We identified 25 eligible patient and 60 controls to investigate the association of the VDR gene polymorphisms FokI, BsmI, ApaI, and Taq I with otosclerosis. The patient and control DNA was genotyped for; VDR Bsm I (rs1544410), VDR Apa I (rs7975232), VDR Taq I (rs731236) and VDR Fok I (rs2228570) gene. Primer, simple probe sequences was genotyped by RT-PCR restriction fragment length polymorphism. RESULTS: There was a statistically significant association between VDR gene and otosclerosis in polymorphism Taq I, Apa I and Bsm I. There was no significant association between VDR gene and otosclerosis in polymorphism Foq I. CONCLUSION: Three polymorphisms (Taq I, Apa I and Bsm I) in the VDR gene appear to be associated to susceptibility to otosclerosis disorder with otosclerosis patients.

Recurrent pacemaker lead thrombosis in a patient with gene polymorphism: a rare case treated with thrombolytic therapy.

Pacemaker (PM)-related thrombosis is an infrequent complication of pacing. We present the case of a 58-year-old man with heart failure and atrial fibrillation who had recurrent episodes of PM lead thrombosis while undergoing anticoagulation therapy. The patient was admitted to the hospital with complaints of dyspnea and palpitation. Echocardiography revealed normal right ventricular dimensions and an enlarged left ventricle with poor contractility and an ejection fraction of 20%. Transesophageal echocardiography demonstrated a large, mobile thrombus in the right atrium that was attached to the PM lead. The patient was successfully treated with a thrombolytic agent. Genetic tests revealed that the patient was a heterozygous carrier of the methylenetetrahydrofolate reductase (MTHFR) gene mutation.

Consensus clinical management guidelines for Alström syndrome.

Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

Dantrolene exerts protective activity in double and triple combination with nimodipine, ruthenium red and basilene blue in bilirubin-induced neurotoxicity in cell culture of rats.

In the present study, dantrolene, nimodipine, basilen blue, and ruthenium red were tested in experimental bilirubin toxicity in cortical cell culture of rats. Neurotoxicity was induced by 10(-4) M bilirubin. Basilen blue in the highest concentration of 10(-4) M was determined as the most protective agent when applied alone. Dantrolene alone was found surprisingly ineffective in all doses tested. But it was found very protective both in double and triple combinations. Nimodipine, basilen blue, and ruthenim red neuroprotective potentials were enhanced by adding dantrolene into the media. Best double combination was determined as dantrolene plus ruthenium red. On the other hand, most useful triple combination was found as dantrolene plus nimodipine plus basilen blue. As a result, dantrolene wasn't found to be effective alone, while it seems most potential compound in combined application in bilirubin-induced neurotoxicity. The importance of calcium intrusion was confirmed in bilirubin-induced neurotoxicity.

The effects of ruthenium red, dantrolene and nimodipine, alone or in combination, in NMDA induced neurotoxicity of cerebellar granular cell culture of rats.

In the present study, we used the L-type calcium channel blocker nimodipine, the endoplasmic reticulum (ER) calcium release blocker dantrolene and the calcium transport blocker in mitochondria ruthenium red (RuR), in NMDA induced neurotoxicity, to observe the most suitable combination for neuroprotection in cerebellar granular cell culture of rat pups. In addition we tested the effect of RuR on intact neuronal cells without adding NMDA into the flask, in order to compare the effects. As was expected, NMDA induced neuronal cell death. In NMDA induced neurotoxicity, RuR was the most neuroprotective agent of all three compounds tested, but interestingly, RuR alone was found to be neurotoxic in non-NMDA treated cultures. RuR showed neuroprotectivity in a dose dependent manner in NMDA toxicity. Dantrolene and nimodipine were also found to have neuroprotective properties in NMDA induced cell death in rat cerebellum. On the other hand, the combined application of the compounds was not found as protective as ruthenium red applications alone. The present study revealed a neurotoxic feature of ruthenium red, however we also demonstrated a neuroprotective role for it in NMDA-mediated neuron culture. This could be interpreted as a result of the partial agonistic effect of ruthenium red.

Polymorphisms in MMP-2 and TIMP-2 in Turkish patients with prostate cancer.

AIM: Prostate cancer is the most commonly diagnosed malignancy and the second most common cause of cancer deaths in the Western male population. Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) modulate the remodeling of the extracellular matrix (ECM). The imbalance between MMPs and TIMPs may lead to an emergence of pathological processes such as cancer. In this study, the association between TIMP-2 (-418 G/C) and MMP-2 (-1306 C/T) polymorphisms and prostate cancer in the Turkish population was investigated. MATERIALS AND METHODS: Sixty-one prostate cancer patients and 46 healthy subjects were included in the study. DNA was isolated from 2 mL of peripheral blood taken from subjects, and genotypes were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The TIMP-2 -418 (GC) genotype was found in 15 cases (32.6%) in the control group and in 9 cases (14.8%) in the patients group, and statistical significance was determined (P = 0.037, OR = 0.346). The MMP-2 -1306 (CT) genotype was found 2.17 times more in the patient group than in the control group (P = 0.149, OR = 2.17). CONCLUSION: Our results show that the TIMP-2 -418 (GC) genotype had a putative protective effect against prostate cancer.

The role of Ruthenium red as a partial agonist in caffeine-induced neurotoxicity in cerebellar granular cell culture of rats.

Caffeine is widely spread and well known as a mild stimulant of the central nervous system. The present study tested the role of caffeine and Ruthenium red on the intact neuronal cells alone and Ruthenium red in caffeine-induced neurotoxicity. One-day-old newborn rats were used to obtain cerebellar cell cultures. Caffeine at a concentration of 1 mM was found to be most toxic. Dead cell scores were 5.9 +/- 0.8 for control, and 56.2 +/- 3.4 for caffeine (p < .001). Ruthenium red alone has also caused the reduction in neuronal cell number 36.1 +/- 4.5 for 10(-5) and 47 +/- 2.7 for 10(-6) M concentrations (p < .001 for both). Interestingly Ruthenium red used in caffeine-induced neurotoxicity has partly diminished the number of dead cells 28.7 +/- 3.2 for 10(-5) and 23.8 +/- 2.27 for 10(-6) M concentrations (p < .001for both). The results suggest that both Ruthenium red and caffeine are neurotoxic alone but, in combination, the neurotoxicity may be reduced through partial agonistic action.

Reactive blue prevented caffeine-induced neurotoxicity by an independent mechanism from intracellular calcium currents in cell culture from auditory cortex of rats.

Neurotoxicity induced by caffeine in auditory-neuron cultures was studied in rat pups. For possible protective effect, reactive blue (RB) alone and in combination with dantrolene were tested in subsequent doses. RB was found to have a U-shape neuroprotective effect in caffeine neurotoxicity. Dantrolene was also tested in combined application in caffeine neurotoxicity. Despite the existing neuroprotection, no additional protection was obtained with various doses of dantrolene. In conclusion, RB may exert neuroprotective effect by increasing intracellular ATP levels in caffeine toxicity. High ATP levels may postpone the toxic cascade. Dantrolene as an endoplasmic reticulum calcium release blocker had no additional protective effect, suggesting that the increased intracellular calcium levels may be involved in later states of the toxic cascade, occurring after the compensatory phase of the cell death.

Apolipoprotein E polymorphism and stroke in a population from eastern Turkey.

Human apolipoprotein E (apo E) alleles are polymorphic with significantly different frequencies among different ethnic groups and have been associated with increased risk of coronary heart disease, and postulated as a major genetic susceptibility locus for Alzheimer's disease. Studies undertaken in different populations have shown different association patterns between apo E genotype and stroke. The aim of this study was to determine the risk of apo E genotype in stroke patients living in the eastern part of Turkey. The apo E genotypes and allele frequencies of 229 individuals from the same geographic area were determined by polymerase chain reaction and restriction fragment length polymorphism, of which 103 were patients with a documented history of stroke without other apparent dementia and 126 age-matched healthy subjects as a control group. A reduced E3/4 genotype frequency was found in subjects with stroke and the E2/3 genotype frequency was elevated in patients with previous stroke. There was no association between apo E epsilon4 allele and stroke. The APOE alleles had divergent effects in this population. Association between APOE (the gene) alleles and stroke in this population may be altered due to interaction with other genetic effects. The effects of APOE alleles and genotypes require further study in different populations.